Zero vergence ultrasound waves for sonodynamic therapy

ABSTRACT

Disclosed are methods of obtaining zero vergence ultrasound waves for providing sonodynamic therapy with ultrasound waves. The method includes coupling a sonodynamic therapy device with an array of flat piezoelectric transducers to a skin surface. A controller is configured to generate an electrical drive signal at a frequency, modulate the drive signal, and drive the transducer with the modulated drive signal at the frequency to produce a zero vergence ultrasound wave to produce an average acoustic intensity sufficient to activate a sonosensitizer in a treatment region without damaging healthy cells in the treatment region.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.17/400,011, filed Aug. 11, 2021, which is a continuation of PCTApplication No. PCT/US2020/017983, filed Feb. 12, 2020, and titledNON-INVASIVE SONODYNAMIC THERAPY, which claims priority under 35 U.S.C.§ 119 to U.S. Provisional Patent Application No. 62/805,186, filed, Feb.13, 2019, and titled NON-INVASIVE SONODYNAMIC THERAPY, each of which ishereby incorporated by reference herein in its entirety.

TECHNICAL FIELD

This disclosure relates to a broadly applicable technology platform fortreating lesions using sonodynamic therapy. More particularly, thisdisclosure relates to devices, systems, and methods for treating tumorsand cancer in body parts using sonodynamic therapy.

BACKGROUND OF THE INVENTION

Sonodynamic therapy is a proposed form of treatment using drugs thatonly become cytotoxic upon exposure to ultrasound. Since ultrasound canbe focused into small tissue volumes within the body, this methodprovides a potential means of localizing treatment and reducing the riskof side effects elsewhere in the body. In this respect it is similar tophotodynamic therapy, which uses light for drug activation, and thereare several drugs that have been shown to be sensitive to both light andsound. A potential key advantage of sonodynamic over photodynamictherapy is the much greater tissue depth that can be reachednon-invasively by ultrasound compared to light.

The drug is a sonosensitizing agent (i.e., sonosensitizer) thatpreferentially accumulates in the cells of the lesions. Sonosensitizersinitiate a cytotoxic response in target tissues when exposed toultrasonic energy. Upon activation by the ultrasonic energy, sonodynamictherapy drugs or “sonosensitisers” produce reactive oxygen species (ROS)that generate the cytotoxic effect. The detailed mechanisms of ROSproduction are not fully understood but several studies have indicatedthat acoustic cavitation and the associated thermal, chemical orluminescence phenomena may be involved. They can be used alone or inconcert with other sonosensitizers, many of which are approved by theFood and Drug Administration (FDA) for use in neurosurgical diagnosticimaging or treatment of tumors throughout the body.

The promise of sonodynamic therapy is the ability to treat a lesion,such as a region in an organ or tissue which has suffered damage throughinjury or disease, such as a wound, ulcer, abscess, or tumor, withlevels of ultrasound that are safe for healthy tissue yet lethal tocells within the lesion harboring a sonosensitizer.

In a contemplated minimally invasive sonodynamic process, lesions couldbe treated directly with a catheter placed in situ using a relativelysimple procedure mimicking a biopsy. Getting an acoustic wave to beconsistent and omnidirectional from a small, needle-like catheter devicecan present technical challenges in some instances. The small diameterof the catheter device, necessary for a minimally invasive procedure,can limit the aperture size for any element acoustically radiatingaxially from the tip. Because of this, the field strength can fall offdue to spherical divergence. Even the acoustic wave emitted radiallyfrom a sufficiently long transducer falls off cylindrically.

Because of the acoustic intensity falling off due to divergence, theacoustic wave near the catheter device may need to be relatively high tohave acoustic intensities sufficient for activating a sonosensitizerseveral centimeters away from the catheter device. These higherintensities near the catheter device may even be enough to causeindiscriminant cell death close to the catheter device, creating anecrotic region around the catheter device. If this “necrotic” region ofthe catheter device were unavoidable, it can limit the locations of thebody where the catheter device can be placed and limit the number ofpatients eligible for treatment.

High intensity focused ultrasound (HIFU) provides a non-invasivetreatment of lesions using intensities of 500 W/cm² to 20000 W/cm²precisely pinpointed over just a few cubic millimeters to cause thermalablation of the tissue. HIFU techniques can ablate tissue non-invasivelyby heating the tissue to temperatures above 42° C. causing necrotic celldeath. The levels of ultrasound used in this procedure are by designlethal to all cells within the ultrasound focus, therefore with thisapproach it is not possible to provide broad coverage that discriminatesbetween healthy tissue and diseased tissue.

Additional challenges of non-invasive techniques employing sonodynamictherapy can be the strong attenuation and reflection of acousticpressure from the patient's body, in particular the skull when treatingsoft tissue and bone. The impedance mismatch between water/skin and boneis significant resulting in strong reflection at the skin-bone and thebone-brain interfaces. The attenuation coefficient of the skull can alsobe quite high resulting in losses due to absorption and scatteringwithin the skull.

The following disclosure describes various sonodynamic therapyapparatuses, systems, and methods for a completely non-invasivetreatment that can penetrate deep into the body.

SUMMARY

An illustrative non-invasive approach to sonodynamic therapy includeslocating several ultrasound transducers or a single transducer withmultiple elements outside of the body part used to transmit acousticwaves through the skin and into the body part The size of thetransducers can allow incident acoustic waves to be roughly planar andnot suffer from as much divergent loss as cylindrical or sphericaldivergence. In one aspect, the acoustic waves generated by severalultrasound transducers or several elements of a single transducerconverge to allow the wavefronts to constructively interfere.Additionally, the total surface area of acoustic elements can allow theenergy transmission to split up amongst many elements instead ofrequiring all the energy to come from a single element.

Clinically speaking, such a system can improve the experience ofpatients. It is non-invasive, so the cost and risk of surgery,infection, and hemorrhage is eliminated as well as the cost andcomplexity of health care is greatly reduced. Preparing a patient fortreatment can take significantly less time. The therapy may last 30minutes to an hour in a non-surgical clinic setting, such as an oncologyclinic. A single practitioner can monitor several patients at the sametime. Because the risk of the device is lower, this may open the door tomore frequent treatment, early treatment within a disease progression,and treatment of less lethal disease.

The illustrative non-invasive apparatuses, systems, and methodsdescribed in the following disclosure can use relatively low acousticintensity over a broader treatment area versus conventional methods. Theillustrative non-invasive techniques discussed hereinbelow producenon-thermally ablative temporal average acoustic intensities in theranges of about 0.1 to about 50 W/cm², or about 0.2 to about 20 W/cm²,or about 0.5 W/cm² to about 8.0 W/cm² over most or all of the body partbeing treated for lesions such as a region in an organ or tissue whichhas suffered damage through injury or disease, such as a wound, ulcer,abscess, or tumor. Unless otherwise specifically stated, the terms“about” and “generally,” with respect to values, means within 10% of theleast significant unit. For example, “about 0.1” means between 0.09 and0.11.

BRIEF DESCRIPTION OF THE DRAWINGS

The following drawings are illustrative of particular aspects of thepresent disclosure and therefore do not limit the scope of the appendedclaims” The drawings are intended for use in conjunction with theexplanations in the following description. The disclosed aspects willhereinafter be described in conjunction with the appended drawings,wherein like numerals denote like elements.

FIG. 1 is a perspective view of a transcranial sonodynamic therapydevice with a shell having multiple transducers and a cooling systemplaced over the head of a patient, according to at least one aspect ofthe present disclosure.

FIG. 2 is a perspective view of a transcranial sonodynamic therapydevice with multiple transducers and a cooling system placed over thehead of a patient, according to at least one aspect of the presentdisclosure.

FIG. 3 is a partial cutaway view of a transcranial sonodynamic therapydevice placed over the head of a patient showing a partial view of themultiple transducers, according to at least one aspect of the presentdisclosure.

FIG. 4 is a schematic view of a transducer with a lens defining aconcave surface, according to at least one aspect of the presentdisclosure.

FIG. 5 is a schematic view of a transducer with a lens defining a convexsurface, according to at least one aspect of the present disclosure.

FIG. 6 is a schematic view of a transducer with multiple elements thatcan be individually energized to produce a variety of acoustic waves,according to at least one aspect of the present disclosure.

FIG. 7 is a bottom view of a transducer having an internal elementsurrounded by concentric rings, according to at least one aspect of thepresent disclosure.

FIG. 8 is a bottom view of a transducer having internal elementsarranged in 2-dimensional (2D) grid array, according to at least oneaspect of the present disclosure.

FIG. 9 is a diagram of two acoustic ultrasonic pulses without delay thatconstructively interfere, according to at least one aspect of thepresent disclosure.

FIG. 10 is a diagram of a pulse packet made of a sine wave signalmodulated by a Gaussian pulse signal, according to at least one aspectof the present disclosure.

FIG. 11 is a partial cutaway view of a transcranial sonodynamic therapydevice placed over the head of a patient showing a partial view of theskull and brain of the patient and multiple transducers with onetransducer emitting energy into the brain of the patient, according toat least one aspect of the present disclosure.

FIG. 12 is a chart showing an intensity transmission ratio acrossmultiple frequencies, according to at least one aspect of the presentdisclosure.

FIG. 13A is a chart showing a transmission and reflection ratio at 1 MHzversus skull thickness in millimeters, according to at least one aspectof the present disclosure.

FIG. 13B is a chart showing a transmission and reflection ratio at 1 MHzversus skull thickness in wavelengths, according to at least one aspectof the present disclosure.

FIG. 14A is a chart showing an intensity transmission ratio as afunction of frequency, according to at least one aspect of the presentdisclosure.

FIG. 14B is a chart showing a reflection ratio as a function offrequency, according to at least one aspect of the present disclosure.

FIG. 15 is a chart showing the field strength of a planar wave into amulti-tissue skull model, according to at least one aspect of thepresent disclosure.

FIG. 16 is a chart showing the energy absorbed ratio of a freshlyexcised human skull at multiple frequencies, according to at least oneaspect of the present disclosure.

FIG. 17 is a partial cutaway view of a transcranial sonodynamic therapydevice placed over the head of a patient showing a partial view of themultiple transducers and a full view of the cooling system, according toat least one aspect of the present disclosure.

FIG. 18 is perspective view of a patient interface, according to atleast one aspect of the present disclosure.

FIG. 19 is a chart showing the relative sensitivity plot of an infrared(IR) temperature sensor, according to at least one aspect of the presentdisclosure.

FIG. 20 is a block diagram of a general non-invasive sonodynamic therapysystem, according to at least one aspect of the present disclosure.

FIG. 21 is an illustrative diagram of the sonodynamic therapy systemshown in FIG. 18 , according to at least one aspect of the presentdisclosure.

FIG. 22 is a schematic diagram of the sonodynamic therapy system shownin FIGS. 18 and 19 , according to at least one aspect of the presentdisclosure.

FIG. 23 is a schematic diagram of a sonodynamic therapy system withseparate transmitting and receiving transducers, according to at leastone aspect of the present disclosure.

FIG. 24 is a schematic diagram of a sonodynamic therapy system with asingle transmitting and receiving transducer, according to at least oneaspect of the present disclosure.

FIG. 25 is an overview of a sonodynamic therapy process, according to atleast one aspect of the present disclosure.

FIG. 26 is a diagram of a cancer cell illustrating the initial stage ofselective accumulation of a sensitizer, according to at least one aspectof the present disclosure.

FIG. 27 is a diagram of the cancer cell illustrating the increasedselective accumulation of a sensitizer, according to at least one aspectof the present disclosure.

FIG. 28 is a diagram of the cancer cell shown in FIGS. 24 and 25undergoing sonodynamic therapy, according to at least one aspect of thepresent disclosure.

FIG. 29 is a diagram illustrating the process of sonoluminescence,according to at least one aspect of the present disclosure.

FIG. 30 is a schematic diagram of a cancer cell illustrating theselective accumulation of a sensitizer, according to at least one aspectof the present disclosure.

FIG. 31 is a schematic diagram of the cancer cell shown in FIG. 28undergoing sonodynamic therapy, according to at least one aspect of thepresent disclosure.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The following detailed description is exemplary in nature and providessome practical illustrations and examples. Those skilled in the art willrecognize that many of the noted examples have a variety of suitablealternatives. A number of various exemplary transcranial sonodynamictherapy devices are disclosed herein using the description provided asfollows in addition to the accompanying drawings. Each of the aspectsdisclosed herein can be employed independently or in combination withone or more (e.g., all) of the other aspects disclosed herein.

Prior to launching into a description of the figures, the presentdisclosure first turns to a general description of various aspects ofnon-invasive sonodynamic therapy systems. In one aspect, the presentdisclosure is directed to a system for sonodynamic therapy. The systemcomprises a transducer, a patient interface to acoustically couple thetransducer to a patient, and a controller coupled to the transducer. Thecontroller is configured to generate an electrical drive signal from aset of modulated acoustic wave parameters, modulate the drive signal,and drive the transducer with the modulated drive signal at a frequencyto produce a modulated acoustic wave to produce an acoustic intensitysufficient to activate a sonosensitizer in a treatment region.

In another aspect, the present disclosure is directed to another systemfor sonodynamic therapy. The system comprises a first transducer, asecond transducer, and a controller coupled to the first and secondtransducers. The controller is configured to generate a first electricaldrive signal from a set of modulated acoustic wave parameters, generatea second electrical drive signal from the set of modulated acoustic waveparameters, drive the first transducer at the first electrical drivesignal to produce a first acoustic wave, and drive the second transducerat the second electrical drive signal to produce a second acoustic wave.The first and second acoustic waves are combinable to produce anacoustic intensity sufficient to activate a sonosensitizer in atreatment region.

In yet another aspect, the present disclosure is directed to yet anothersystem for sonodynamic therapy. The system comprises a plurality oftransducers and a controller coupled to the plurality of transducers.The controller is configured to generate a plurality of electrical drivesignals from a set of modulated acoustic wave parameters and drive theplurality of transducers at the plurality of electrical drive signals toproduce a plurality of modulated acoustic waves. The plurality ofmodulated acoustic waves are combinable to produce an acoustic intensitysufficient to activate a sonosensitizer in a treatment region.

The following description provides illustrative examples of applicationsof non-invasive sonodynamic therapy techniques to treat tumors withinthe brain. It will be appreciated, however, that such techniques can beapplied to treat tumors within other body parts. Turning now to FIG. 1 ,human skulls can vary by gender and anatomical location. One aspect ofthe present disclosure provides a non-invasive sonodynamic therapydevice 100 as shown in FIG. 1 . The non-invasive sonodynamic therapydevice 100 may comprise a shell 110 with transducers 150 that canprovide predictable and consistent insonication despite thesevariations. The shell 110 may comprise a rigid material. Known relativepositions of the transducers 150 can allow for imaging of the head, evenin low resolution with large transducers 150. The illustrated aspect mayrequire a mobile stand to hold in position on the patient while he/shewaits in a seated or supine position. The rigid shell 110 may be alightweight helmet that can be worn by the patient during treatment,allowing for predictable placement of the transducers 150 with littleinfrastructure requirements.

The non-invasive sonodynamic therapy device 100 may comprise a flexibleshell 110 (e.g., a helmet) with transducers 150 placed over aliquid-cooled skull cap 160 as described further elsewhere herein,requiring little infrastructure to support the array of transducers 150.It may be possible for the patient to don the skull cap 160 and shell110 in any chair while he/she waits for treatment to complete. Thelightweight design may minimize neck pain from the patient holding uphis/her head for extended periods with the weight of the transducers 150and cooling cap. The flexible shell 110 can conform to the shape of eachskull. Such a device may account for subtle variations betweentreatments depending on the shape of each patient's head curving sometransducers 150 more inward or outward.

The non-invasive sonodynamic therapy device 100 may comprise rigid orflexible patches with several transducers 150 that can be removablyapplied to the head. Such an aspect may require clinicians to apply eachpatch individually. Having separate patches can allow for some treatmentflexibility without requiring each transducer 150 to be planned andplaced individually. An illustrative non-invasive sonodynamic therapydevice 100 may minimize sores caused by adhering patches to the headrepeatedly, which may be a particular concern for older and sickerpatients.

The non-invasive sonodynamic therapy device 100 may comprise patcheswith single transducers 150 that can be removable applied to the head.Individual transducers 150 can provide the most treatment flexibility.Such a device may require a detailed process for planning to apply andapplying the transducers 150. Given the additional flexibility, theillustrative non-invasive sonodynamic therapy device 100 may accommodatefor greater usability risk.

The size and shape of the transducers 150, as can be seen in FIG. 2 ,may vary across various disclosed aspects. For a cost-effective andsimple system, larger transducers 150, which produce directionalacoustic waves, may be used. Large transducers 150 can be made lessdirectional by applying to each transducer 150 an acoustic lens thatbends the acoustic waves as described further elsewhere herein. For asystem that can conform to the head, smaller transducers 150, which canradiate more broadly than larger transducers 150, can be used. Suchsmall transducers 150 can have a greater ability to image or beam steeras an array.

FIG. 3 is a partial cutaway view of a transcranial sonodynamic therapydevice 100 placed over the head of a patient showing a partial view ofthe multiple transducers 150, according to at least one aspect of thepresent disclosure. Instead of focusing an acoustic wave 200 to a smallpoint, the acoustic wave 200 can be defocused to minimize the spatialvariation of the acoustic wave intensity in the brain.

The size and shape of the transducers 150 may defocus or focus eachtransducer 150. As used herein, the term focused refers to an acousticwavefront that is more convergent than a wavefront produced by atransducer 150 with a planar emitting surface and the term defocusedrefers to an acoustic wavefront that is more divergent than a wavefrontproduced by a transducer 150 with a planar emitting surface. Whether alens needs to be concave or convex to make a wave more divergent dependson whether the acoustic wave is transitioning from a region of lowacoustic impedance to a region of high acoustic impedance or theacoustic wave is transitioning from a region of high acoustic impedanceto a region of low acoustic impedance. In this regard, if a lens is madeof a material with higher acoustic impedance than the target medium(water/tissue), the acoustic wave originates in the high-impedancematerial and transitions to the low-acoustic impedance target medium. Ifthe lens is concave, the lens will “focus” the acoustic wave to make itmore convergent. If the lens is convex, the lens will “defocus” theacoustic wave to make it more divergent.

FIG. 4 is a schematic view of a transducer 150 with a lens 302 defininga concave surface 304, according to at least one aspect of the presentdisclosure. The lens 302 may be acoustically coupled to the transducer150 or may be formed integrally therewith. In the illustrated example,the lens 302 is made of a material with higher acoustic impedance thanthe target medium (water/tissue) such that the acoustic wave 306originates in the high-impedance material and transitions to thelow-acoustic impedance target medium causing the acoustic wave 306“focus” or converge to the target tissue.

FIG. 5 is a schematic view of a transducer 150 with a lens 308 defininga convex surface 310, according to at least one aspect of the presentdisclosure. The lens 308 may be acoustically coupled to the transducer150 or may be formed integrally therewith. In the illustrated example,the lens 308 is made of a material with higher acoustic impedance thanthe target medium (water/tissue). Accordingly, an acoustic wave 312originates in the high-impedance material and transitions to thelow-acoustic impedance target medium causing the acoustic wave 312 to“defocus” or diverge to the target tissue.

The focus of the transducers 150 also depends on the material and shapeof the lens (not shown). Using a lens 302, 308 allows the transducers150 to be flat, which may minimize manufacturing costs. Both the lens302 with the concave surface 304 and the lens 310 with the convexsurface 310 may be configured to produce a fixed focus.

It may be possible to produce a lens that can adjust its shape to createdifferent focuses. It may be possible to create an elastic, fluid-filledpocket that functions as a lens. The fluid can be pumped in or out ofthe lens to adjust shape of the pocket and thus the focus of thetransducers.

FIG. 6 is a schematic view of a transducer 150 with multiple elements150 a-150 h that can be individually energized to produce a variety ofacoustic waves, according to at least one aspect of the presentdisclosure. As shown in FIG. 6 , multiple transducer elements 150 a-150h can be arranged in an array to produce converging, diverging, orplanar, acoustic waves. For examples, the transducer elements 150 a-150h can be activated in a predetermined sequence to selectively generateconvergent/divergent/planar acoustic waves, such as, for example, theconvergent acoustic wave 314, shown in FIG. 4 , or a divergent acousticwave 312 shown in FIG. 5 . To generate a converging acoustic wave 314,for example, the outer transducer elements 150 a, 150 h are initiallyenergized and after a time delay the adjacent inner transducer elements150 b, 150 g are energized. The next adjacent inner transducer elements150 c, 150 f are energized after a second time delay. Finally, the innertransducer elements 150 d, 150 e are energized after a third time delay.This pattern can be repeated to generate the converging acoustic wave314. The first, second, and third time delays may be equal or may varyin order to generate more complex acoustic waves. Alternatively, thetransducer elements 150 a-150 h may be energized in reverse order toproduce a diverging acoustic wave using equal or different time delays.The transducer elements 150 a-150 h can be interchangeably configured totransmit or receive acoustic waves.

FIG. 7 is a bottom view of a transducer 400 having an internal element420 surrounded by concentric rings 410, according to at least one aspectof the present disclosure. Each transducer 150 can be adapted andconfigured to produce an acoustic wave with variable focus. One way toaccomplish this can be with each transducer 400 having concentric rings410 (e.g., an annular array) as shown in FIG. 7 . Each concentric ring410 can be driven with a different signal. To focus the acoustic wave,the signal going to the inner element 420 may be progressively moredelayed than the outer of the concentric ring 410. The acoustic wavesfrom each concentric ring 410 may converge at a point. To defocus theacoustic wave coming from an annular array, the acoustic wave at theouter of the concentric rings 410 may be progressively more delayedrelative to the inner element 420. One way to make an annular array canbe with concentric rings 410 of equal area. In another aspect, theannular array may comprise concentric rings 410 of unequal area.

FIG. 8 is a bottom view of a transducer comprising internal elements 452arranged in 2-dimensional (2D) grid array 450, according to at least oneaspect of the present disclosure. Each internal element 452 of the 2Dgrid transducer array 450 can be driven with a different signal. Toproduce a converging acoustic wave (e.g., “focus”), the signal appliedto the inner element 454 may be progressively more delayed than thesignal applied to the outer elements of the 2D grid transducer array450. To produce a diverging acoustic wave (e.g., “defocus”), theacoustic wave produced by the outer elements 452 may be progressivelymore delayed relative to the inner element 454. In one aspect, each ofthe internal elements 452 of the 2D grid transducer array 450 may definean equal area. In another aspect, each of the internal elements 452 ofthe 2D grid transducer 450 array may define an unequal area.

In one aspect, the transducer 150, 400, 450 may be implemented as asingle transducer comprising multiple piezoelectric elements withacoustically/electrically-independent sections arranged in an array. Inother aspects, the transducer 150, 400, 450 may be implemented asdifferent transducers working in a coordinated manner. There is littleor no distinction from a physics perspective between a single transducerwith multiple elements and different transducers working incoordination. The elements of an array can be sized on the order of awavelength. In one aspect, the transducer 150, 400, 450 may beimplemented as a single transducer comprising a plurality of elementsimplemented as an annular array as shown in FIG. 7 or as a grid array asshown in FIG. 8 . In another aspect, the transducer 150, 400, 450 may beimplemented as a plurality of individual transducers.

In one aspect, each of the transducers 150, 400, 450 shown in FIGS. 4-8, or elements thereof, are non-invasive and may be implemented in asuitable size and shape to fit on the body part of the patient. Also,the individual number and arrangement of transducer elements may beselected to fit on the body part of the patient. In one aspect, thetransducer 150, 400, 450, or elements thereof, may be made ofpiezoelectric or single crystal material which converts electricalenergy to ultrasonic energy. The transducer 150, 400, 450 also canreceive back ultrasonic energy and converts it to electrical energy.Each of the transducers 150, 400, 450, or elements thereof, may beadaptively focused to produce acoustic waves by collaborative transducerperformance. For example, each of the transducers 150, 400, 450, orelements thereof, may be selectively controlled to operate either as atransmitter or as a receiver by a controller as described hereinbelow.Further, each of the transducers 150 400, 450, or elements thereof, maybe selectively energized and actuated to produce convergent, divergent,or planar acoustic waves as discussed in more detail in the followingdescription.

With reference now to FIGS. 4-8 , in one aspect, the acoustic waveproduced by the transducer 150, 400, 450 may be defined by vergence—ameasure of the curvature of the acoustic wavefront A negative vergenceis when the acoustic wavefront propagates away from a point (i.e.,divergence). A positive vergence is when the acoustic wavefrontpropagates towards a point (i.e., convergence). A zero vergence is aplanar acoustic wavefront that does not converge or diverge. Vergence isa property of a single acoustic wavefront. A single converging/divergingacoustic wavefront may be produced by multiple elements of a transducer150, 400, 450 (e.g., a transducer comprising an annular array 400 or agrid array 450).

In one aspect, the acoustic wave produced by the transducer 150, 400,450 may be characterized by phase and/or delay. The phase and/or delaymay be employed to measure a relative shift in time between two acousticwaves. The phase is the amount of time shifted between two acousticwaves relative to the period of the two acoustic waves (e.g., measuredin degrees or radians). The delay is a measure of the amount of timeshifted between two acoustic waves (e.g., measured in milliseconds).Delay and phase are often used interchangeably. For example, although“delay” may be described in units of degrees or radians, it is wellunderstood that “delay” is an abbreviation for “phase delay.” For asingle acoustic wave pulse, it is clearer to discuss delay between thepeaks of two acoustic wave pulses in terms of time because a phase shiftrequires a periodic signal. For repeating acoustic waves, the relativedelay is often measured terms of phase. For continuous, periodicacoustic waves, delaying an integer number of periods should have noeffect because, by definition, a periodic signal exhibits symmetry overfull period shifts. For pulses of a repeating acoustic wave (e.g., 1000cycles of a sine wave), the acoustic wave can be delayed by an integernumber of cycles. The beginning and end of the wave packet will havesome edge effect when one signal begins/ends before the other. In themiddle of the two wave packets, there will be no effect (provided thesignals still overlap).

In one aspect, the transducers 150, 400, 450 may be adapted andconfigured to produce a “focused” acoustic wave by producing aconvergent acoustic wave that converges to a point. In another aspect,the transducers 150, 400, 450 may be adapted and configured to produce a“defocused” acoustic wave, e.g., a divergent acoustic wave. In otheraspects, the transducers 150, 400, 450 may be adapted and configured toproduce a planar acoustic wave (e.g., zero vergence) where the acousticwave is neither “defocused” nor “defocused.”

In various aspects, the transducers 150, 400, 450 may be driven atultrasonic frequencies in a range of about 20.00 kHz to about 12.00 MHz.More particularly, the transducers 150, 400, 450 may be driven atultrasonic frequencies in a range of about 650.00 kHz to about 2.00 MHz.In a preferred range, the transducers 150, 400, 450 may be driven atultrasonic frequencies in a range of about 900.00 kHz to about 1.20 MHzand more preferably at about 1.06 MHz.

FIG. 9 is a diagram 470 of two acoustic ultrasonic pulses 472, 474without delay that constructively interfere, according to at least oneaspect of the present disclosure. As previously described, thetransducers 150, 400, 450 may be adapted and configured to produce a“focused” acoustic wave by coordinating time between multiple acousticwavefronts and producing wavefronts that constructively interfere. Thecoordination of acoustic wavefronts is independent of the vergence ofthe acoustic wavefronts. The point at which the wavefronts focus can beadjusted by delaying one signal relative to another. The diagram 470shown in FIG. 9 shows two pulses 472, 474 produced without any relativedelay. The two pulses 472, 474 constructively interfere when they reachthe center and may be said to be focused in the center to produce acombined pulse 474. If the acoustic pulse 472 on the left is delayedrelative to the acoustic pulse 474 on the right, the two pulses 472, 474would meet at a point left of center, thus shifting the point ofconstructive interference to the left of center. Likewise, if theacoustic pulse 474 on the right is delayed relative to the acousticpulse 474 on the right, the two pulses 472, 474 would meet at a point tothe right of center, thus shifting the point of constructiveinterference to the right of center.

In another aspect, a mixture of convergent/divergent/planar acousticwaves may be timed to meet and constructively interfere at one location.A divergent acoustic wave may be timed to meet and destructivelyinterfere at one location.

Control of the converging and diverging wavefronts produced by thetransducers 150, 400, 450 can be taken into account as part ofpretreatment planning. Based on inputs from the pretreatment planningprocesses the controller can adaptively modulate the transducers 150,400, 450 such that the acoustic wavefronts coordinate to preferentiallytarget a desired treatment region. In one aspect a digital imaging andcommunications (DICOM) image from a computerized tomography (CT) orother imaging source could be an input to the device controller togenerate customized modulation pattern that optimizes the treatmentregion for a particular patient. In another aspect the pretreatmentplanning could include selection of a preferred transducer type orarrangement of transducer types that will produce an optimized treatmentregion for a particular disease state. In another aspect, the patientinterface may come in various arrangements that can be selected duringpretreatment planning to coordinate the transducer(s) in preferredarrangement for treatment.

“Defocused” acoustic waves may be measured based on the volume of tissuetreated according to the number of nodes and antinodes. A histogram ofintensities or pressures over some volume may be employed to measure“defocused” acoustic waves. In one aspect, a dose-volume histogram maybe employed in planning sonodynamic therapy. Alternatively, a cumulativehistogram may be employed.

FIG. 10 is a diagram of an acoustic pulse packet 480 made of a repeatingsignal modulated by a Gaussian pulse signal, according to at least oneaspect of the present disclosure. In one aspect, the acoustic wavegenerated by the transducer 150, 400, 450 may be amplitude modulated.The acoustic pulse packet 480 may be produced by modulating a repeatingsignal, such as a sine wave, with a Gaussian pulse where the repeatingsignal is independent from the Gaussian pulse. When the transducer 150,400, 450 is driven by the modulated signal, it produces an acousticpressure pulse 482 where the amplitude varies according to the envelope484, which is in the form of the Gaussian pulse. Although, in theillustrated example, the repeating signal is a sine wave, the repeatingsignal may take many forms. The repeating signal may be modulated byrectangular pulses, triangular pulses, or pulses of a predefinedmathematical shape. In addition to amplitude modulation, a repeatingsignal may be pulse-width modulated, duty-cycle modulated, phasemodulated, frequency modulated, randomized phase modulated, or may bemodulated using any suitable modulation technique to produce a desiredacoustic pulse packet The repeating signal may include inter or intrapulse variations.

FIG. 11 is a partial cutaway view of a transcranial sonodynamic therapydevice placed over the head of a patient showing a partial view of theskull 510 and brain of the patient and multiple transducers 150 with onetransducer emitting energy 200 into the brain of the patient, accordingto at least one aspect of the present disclosure. It can be possible totake measurements or get a rough image of the skull 510 as shown in FIG.11 . This can be facilitated if the transducers 150 are fixed to a rigidshell and their relative positions and orientations are known. Roughmeasurements can be used to adjust the treatment algorithm by measuredparameters such as skull thickness, “t.” Each transducer 150 may sendout an acoustic pulse and listen for an echo. The echoes can be used fora quick estimate of the skull thickness, “t,” under each transducer 150.For treatment of tumors in other body parts of the patient, thesonodynamic therapy device may be adapted and configured to the coupleto the body of the patient.

For designs with transducers 150 that have an adjustable focus, thefocus of each transducer 150 can be set beforehand with treatmentplanning. Alternatively, the transducers 150 can adjust their focusautomatically based on temperature readings of the head or based onskull thickness, “t,” measurements.

The amplitude of the electrical drive signal driving the transducers 150can be controlled or modulated. In some cases, it can be beneficial tomodulate the electrical drive signal driving the transducers 150 basedon the temperature of the head or other body part being treated. Forexample, if the temperature sensors are detecting a sharp rise intemperature, the amplitude of the transducers 150 can be decreased, shutoff for a period, or the duty cycle can be decreased. By modulating theintensity of the acoustic pulses, the temporal average acousticintensity may be regulated to activate the sensitizer while maintainingthe temperature of the tumor cells below a temperature (e.g., below 42°C.) capable of causing thermal damage to the cell and in somecircumstances necrotic cell death. In another aspect, sonodynamictherapy can function at a variety of different frequencies. Eachfrequency can transmit through a skull 510 efficiently with certainthicknesses of skulls. Using a variety of frequencies can allow anon-invasive sonodynamic therapy device 100 to operate on a broad rangeof skull thicknesses, “t.”

In aspects where the transducers 150 can operate at multiplefrequencies, the frequency of each transducer 150 can be selectedmanually or automatically. As stated in the foregoing description, thetransducers 150 may be driven at ultrasonic frequencies in a range ofabout 20.00 kHz to about 12.00 MHz. More particularly, the transducers150 may be driven at ultrasonic frequencies in a range of about 650.00kHz to about 2.00 MHz. In a preferred range, the transducers 150 may bedriven at ultrasonic frequencies in a range of about 900.00 kHz to about1.20 MHz and more preferably at about 1.06 MHz. The frequencies can bepreselected by a physician. The frequencies can be selected based on ameasurement of head anatomy (e.g. skull thickness, “t”). For example,each transducer 150 can send out a sequence of pulses to measure thethickness of the skull 510 closest to it. Based on the result of theskull thickness, “t,” measurement, an algorithm can be used to selectfrequencies from a set of frequencies or from a range of frequenciesthat may be best suited for the skull thickness, “t,” and energize thetransducers 150 accordingly.

The size and shape of the transducers 150, as can be seen in FIG. 2 ,may vary across various disclosed aspects. For a cost-effective andsimple system, larger transducers 150, which may have directionalacoustic waves, may be used. Large transducers 150 can be made lessdirectional by applying to each transducer 150 an acoustic lens thatbends the acoustic waves as described further elsewhere herein. For asystem that can conform to the skull, smaller transducers 150, which canradiate more broadly than larger transducers 150, can be used. Suchsmall transducers 150 can have a greater ability to image or beam steeras an array.

Instead of focusing an acoustic wave 200 to a small point, the acousticwave 200 can be defocused to minimize the spatial variation of theacoustic wave intensity in the brain as shown in FIG. 4 . The size andshape of the transducers 150 may defocus or focus each transducer 150.Defocused transducers can be formed using a transducer 150 with a convexemitting surface 310 as seen in FIG. 5 . As seen in FIG. 4 , design ofthe transducers can focus the sound from each transducer 150 using aconcave emitting surface 304 with a center of curvature where the soundcan focus. As shown in FIG. 6 , an array of transducers 150 a-150 h canbe used to generate acoustic waves that are convergent, divergent, ormore complex.

Each transducer 150 can cycle through several frequencies so that atleast one of the frequencies can transmit nearly optimally for the givenskull thickness, “t.” Each transducer 150 may also sweep continuouslyfrom one frequency to another. A frequency can be pre-selected for eachtransducer 150 based on the thickness of skull 510 nearest to it (e.g.,during treatment planning by the physician). Prior to treatment, eachtransducer 150 can transmit test signals and monitor the reflected soundto automatically determine which frequency or frequencies can work bestfor that one of the transducers 150. The test signals can be used tomeasure the skull thickness, “t,” directly by measuring delays in pulseechoes, or they can be used to detect the relative amount of reflectedacoustic energy.

Each transducer 150 can be made up of a broad-spectrum ultrasonictransducer or can be made up of several smaller transducers (e.g.,piezo-electric elements as shown in FIGS. 6-8 ) designed to work atparticular frequencies. Each transducer 150 can have an elementspecifically designed to monitor the waves reflected from the head. Inthe case where the transducers 150 are made of several smallertransducers 150, while one transducer 150 is transmitting sound, theother transducers 150 may be used to monitor the incoming acousticpulses.

Of all the frequencies that work with sonodynamic therapy, a subset offrequencies can be selected to best cover a range of common skullthicknesses, “t.” Frequencies that share many common factors (e.g.,harmonics such a 1 MHz and 2 MHz) may not make good choices to cover themost number of skull thicknesses because many of the transmission peaksbetween the two frequencies can be shared. Frequencies without many orany common factors (e.g., coprime numbers) may make for good choices forfrequencies because the transmission peaks can occur at different skullthicknesses.

FIG. 12 is a chart 700 showing an intensity transmission ratio acrossmultiple frequencies, according to at least one aspect of the presentdisclosure. As shown in FIG. 12 , the transmission of 5 differentfrequencies across different skull thicknesses between 4 mm and 9 mm. Afirst frequency 702 at 1.107 MHz, a second frequency 704 at 1.052 MHz, athird frequency 706 at 1.000 MHz, a fourth frequency 708 at 0.961 MHz,and a fifth frequency at 0.898 MHz. There can be good coverage ofdifferent skull thicknesses. In this example, each skull thickness canhave at least one frequency that can transmit 75% or more of its energy.This can be accomplished with frequencies between 898 kHz and 1.107 MHz,a range of only 0.2 MHz

Transmission of sound through an absorbing layer of tissue may notmonotonically decrease as function of thickness. Instead, transmissioncan be enhanced when the thickness of the skull is a multiple of halfthe wavelength of the sound in that layer. Similarly, when the thicknessof the skull is an odd multiple of quarter wavelengths (halfway betweenA/2 multiples), the transmission can be reduced.

FIG. 13A is a chart 720 showing an intensity transmission and pressurereflection ratio at 1 MHz versus skull thickness in millimeters and FIG.13B is a chart 730 showing a transmission and reflection ratio at 1 MHzversus skull thickness in wavelengths, according to at least one aspectof the present disclosure. As shown in FIGS. 13A and 13B, thetransmission of a 1 MHz soundwave through various skull thicknesses.FIG. 7A shows the skull thickness in millimeters and FIG. 13B shows theskull thickness in multiples of wavelength of the intensity transmissionratio 722 and the reflection ratio 724. The intensity transmission ratio722 can reach a peak whenever the skull is a multiple of a halfwavelength. Likewise, the ratio of sound reflected shown as thereflection ration 724 can be at a minimum whenever the skull is amultiple of a half wavelength.

The intensity transmission ratio 722 and the pressure reflection ratio724 can be functions of both the skull thickness and the frequency. FIG.14A is a chart 740 showing an intensity transmission ratio 722 as afunction of frequency and FIG. 14B is a chart 750 showing a reflectionratio 724 as a function of frequency, according to at least one aspectof the present disclosure. To the right of the chart 740 in FIG. 14A isa scale 742 of the intensity transmission ratio 722 ranging from 0.0 to1.0 and the right of the chart 750 in FIG. 14B is a scale of thereflection ratio 724 ranging from −1.0 to +1.0. FIGS. 14A and 14B showhow the intensity transmission ratio 722 and the reflection ratio 724change with skull thickness and frequency. Negative reflection ratioscan be achieved wherever peak transmission may be occurring. Negativereflection ratios can indicate that the reflected wave can be phaseshifted 180° relative to the incident wave. As shown in the chart 740 ofFIG. 14A, the intensity transmission ratio 722 has a maximum ratio 744of about 1.0 and a minimum ratio 746 of about 0.4, which is consistentwith the maximum/minimum ratios shown in charts 720, 730 in FIGS. 13Aand 13B. The chart 750 shown in FIG. 14B shows that the reflection ratio724 has a minimum ratio 754 of about 0.0 and a maximum ratio 756 ofabout 0.8, which is consistent with maximum/minimum ratios shown in thecharts 720, 730 in FIGS. 13A and 13B.

Frequencies that are different by an irrational number may make goodchoices because they can have peak transmissions at differentthicknesses. The golden ratio (e.g., the “most irrational number”) maybe useful in selecting frequencies. It may not be sufficient forselected frequencies' transmission to avoid peaking at the same skullthickness, “t.”

It can also be allowable for two frequencies to share a peaktransmission at a certain thickness, provided that the shared peakoccurs at a skull thickness, “t,” outside of the thicknesses expected tooccur naturally. If the device can select the best frequency (e.g., thegreatest transmission ratio) at each skull thickness, “t,” then to getoptimal coverage across many skull thicknesses, “t,” with a limitednumber of frequencies can mean to maximize the average transmissionratio of the best frequency across the selected skull thicknesses, “t,”or to maximize the minimum transmission ratio of the best frequencywithin the selected skull thicknesses, “t.”

Hair on the patient's head may need to be shaved or shortened to allowfor efficient transmission of sound into the brain. Some aspects mayallow the hair to remain untouched. A comb-like structure can be able topass through hair to contact the skull in many locations to transmitsound. The hair may also be wet and matted down to allow for the soundto transmit relatively unimpeded.

FIG. 15 is a chart 760 showing the field strength of a planar wave 762into a multi-tissue skull model, according to at least one aspect of thepresent disclosure. With reference to FIG. 15 , the skull may absorb alarge proportion of the ultrasonic energy in a short distance. Theinsertion loss 764 (the amount of energy that can be lost by adding theskull into the acoustic wave 200) can be centered around 12 dB. Everyadditional 3 dB worth of loss can correspond to approximately half ofthe energy being reduced. A 12 dB loss can be equivalent to a sixteenthof the energy introduced at the surface of the skin being left at thesurface of the skull. Because of this, the skull may heat up duringtranscranial sonodynamic therapy.

Table 1 is a summary of the parameters that can be used in the model ofthe skull. In addition to the intrinsic acoustic properties of theskull, the skin can be assumed to be 2.5 mm thick, and the skull can beassumed to be around 6.8 mm thick. FIG. 15 shows the acoustic intensityin terms of field strength (dB) as a function of distance within thehead model. The insertion loss 764 highlighted region emphasizes thejumps of energy lost at the interfaces and steep attenuation within theskull.

TABLE 1 Parameters Used In The Model Of The Skull Interface TransmissionLoss Interface Ratio dB Skin-Bone T = 0.650 −1.87 Bone-Skin T - 0.567−2.46 Frequency 1 MHz Attenuation Skin −0.5 dB/(cm-MHz) Bone −11.1dB/(cm-MHz) Brain −1 dB/(cm-MHz) Acoustic Skin 1.99 Kg/sec-m²) × 106Impedance Bone 7.75 Kg/sec-m²) × 106 Brain 1.6 Kg/sec-m²) × 106

The model uses an average of various human skull thicknesses. Thethickness of the “frontal, parietal and occipital bones were (in mm)6.58, 5.37 and 7.56, respectively, for the male; and 7.48, 5.58 and8.17, respectively, for the female.” As mentioned elsewhere herein,human skulls vary considerably by gender and anatomical location. Themodel can represent an average amount of attenuation, but thickersections of skull can have a greater amount of attenuation. In general,every additional 2.7 mm worth of skull can increase the attenuation by 3dB (a factor of 2).

This model can be based on a simple plane wave model impinging on planarlayers of tissue. Each layer of tissue can be assumed to be homogenousand uniform thickness. The effect of the acoustic wavelength (λ)matching with various thicknesses of skull are ignored in this model. Itcan also be assumed that all reflected waves are lost and do not reenterthe brain.

Pichardo et al. investigated the transmission of ultrasound throughfreshly excised human skulls at various frequencies. They report theratio of absorbed energy for seven skulls at several locations at thefrequencies of 0.270, 0.836, and 1.402 MHz. While they did not measurethe energy lost at 1 MHz specifically, their study allows interpolationand estimation that the insertion loss can be centered around 12 dB.Their study also can confirm that the insertion loss can be expected tovary by skull and anatomical location.

FIG. 16 is a chart 770 showing the energy absorbed ratio 772 of afreshly excised human skull at multiple frequencies, according to atleast one aspect of the present disclosure. As shown in FIG. 16 , Pintonet al. also measured the attenuation at 1 MHz of nine points along an 8mm thick section of skull bone and found an insertion loss of 12.6±1.33dB (higher loss due to a thick skull section). Both the simplified headmodel and measurements taken from different laboratories agree that theinsertion loss (the amount of energy lost by adding the skull into themodel) can be centered around 12 dB (a factor of 16) with considerablevariation.

The energy lost as the sound passes through the skull may be convertedinto heat primarily in the skull. The temperature of the skull can beginto heat up and, over time, heat can disperse to nearby tissue. Most ofthe heating can originate at the outer surface of the skull and disperseinto the skin and other layers of bone. Above certain intensities, theblood can be unable to transport enough heat away, and the temperaturein the bone and skin can rise to unsafe levels. Adding more transducersinto the system can decrease the intensity at which this threshold canbe reached because the blood can be warmed by each successive transducerit passes and lose its ability to absorb additional heat from thetissue.

There can be several ways to combat the effects of heating. Inparticular, cooling, intermittent treatment, monitoring, and transducermodulation can be used to reduce the consequences of heating.

FIG. 17 is a partial cutaway view of a transcranial sonodynamic therapydevice placed over the head of a patient showing a partial view of themultiple transducers 150 and a full view of a cooling system 600,according to at least one aspect of the present disclosure. The coolingsystem 600 shown in FIG. 17 may be implemented to keep the temperatureof the skull and surrounding tissue within safe levels. A cooling layer(e.g., of water) may be provided between the transducers 150 and thepatient's head. The cooling layer can be made of a flexible membrane orballoon that can conform to each patient's head. A large cooling layermay be reusable and, thus, may require cleaning between each use.

The cooling system 600 can be made of a flexible cavity (not shown) withan inlet and an outlet for a coolant such as water to circulate. Thehead of the patient can be inserted into a concave shape (e.g., a“bowl”) with an elastic opening. The elastic opening can seal againstthe head of the patient. Water can fill up the space between thepatient's head and the bowl.

Similar to the single cavity design, water can be circulated to keep thetemperature of the water from rising. One advantage of such a system canbe that water in the cooling system 600 can be in direct contact withthe patient's head. The air around the patient's hair can be removed bythe water, which may help couple the ultrasound transducers 150 to thepatient's head.

FIG. 18 is perspective view of a patient interface 650, according to atleast one aspect of the present disclosure. The cooling system 600 canbe a cap 160 with cooling channels 630 distributed throughout. The cap160 can have one long loop of cooling channels 630, or it can haveseveral independent loops. A system with several cooling loops can beconnected to a single inlet and outlet tube via a manifold, or they canbe controlled independently. Water or other heat transfer fluid can becirculated through the cooling channels 630 to exchange heat generatedeither by the transducers 150, the patient's body, or a combinationthereof.

Water can flow past all regions of the head that can absorb heat. Thewater can be pumped to keep the water temperature from rising whichwould decrease the cooling efficacy of the water. Like patches withmultiple transducers 150, each patch may have its own cooling channels630. The cooling channels 630 can be water-filled tubes that may belarger and heavier than the wires going to the transducers 150. Thenumber of unique cooling channels 630 can be optimized to avoidexcessive weight in the cooling layer.

The effect of heating can be readily monitored with temperature sensorsand reduced with the fluid cooling system 600. A layer of cool, degassedwater between the ultrasonic transducers 150 and the head can serve adual function of coupling the head to the transducers 150 andcontrolling the temperature of the skull. Prior to any insonication, thehead can be cooled for several minutes by a constant flow of cool water.Once the treatment begins, the temperature of the skull can be monitoredcontinuously, which can modulate the treatment over the entire skull, orit can individually modulate each transducer 150. Even withoutcontinuous monitoring of the skull temperature, a safe treatmentalgorithm can be devised with intermittent treatment and continuouscooling with a margin of safety for all patients. Intermittent treatmentcan also be more effective than the same effective treatment time donecontinuously due to the rate limiting step of oxygen diffusion aroundthe sonosensitizer.

It can be likely that just surface temperature monitoring can benecessary. In any case, it can be possible to monitor the temperaturethroughout the skull using a variety of thermometry of deep-seatedtissues. Any surface measurements of temperature may need to beinsulated from the cooling layer of water to prevent the probe frombeing dominated by the cooling layer's effect.

The temperature of the patient's head may need to monitored. Iftemperature sensors (not shown) are simply placed between the coolinglayer and the head, the temperature sensor can be reading somecombination of the head temperature and the cooling layer temperature.

There can be several ways that the temperature sensor can be isolatedfrom the temperature of the cooling layer. A layer of insulation can beplaced between the cooling layer and each temperature sensor. In suchinstances, the area around each temperature sensor can receive less orno cooling.

FIG. 19 is a chart 800 showing the relative sensitivity plot 802 of aninfrared (IR) temperature sensor, according to at least one aspect ofthe present disclosure. As shown in FIG. 19 , a temperature probe (notshown) that measures only in one direction (e.g., unidirectional) can beutilized. An example of a unidirectional temperature sensor can be an IRtemperature sensor. IR temperature sensors measure the infrared lightbeing emitted by an object via black body radiation. IR temperaturesensors accept radiation coming in from a small range of angles (e.g.,an acceptance cone). In this application, one or more IR sensors can beoriented so that the cone of acceptance of each sensor can be facing thepatient's head. One or more methods above can be combined to accuratelymonitor the temperature of the patient's head.

FIG. 20 is a block diagram of a general non-invasive sonodynamic therapysystem 900, according to at least one aspect of the present disclosure.The non-invasive sonodynamic therapy system 900 comprises a controller902 coupled to an ultrasonic transducer array 904 to control theoperation of the ultrasonic transducer array 904 to generate a suitableultrasonic acoustic wave. The ultrasonic transducer array 904 is coupledto a patient interface 906 to couple the ultrasonic acoustic waveproduced by the ultrasonic transducer array 904 to a sensitizer 908 thataccumulates in tumor cells within the patient's body. Through a processcalled sonoluminescence, the ultrasonic acoustic wave produces lightthat activates the sensitizer 908 and causes necrosis of the tumorcells.

Sonodynamic therapy treatment employs a sensitizer 908 drug that onlybecome cytotoxic upon exposure to ultrasound. Upon activation,sonodynamic therapy drugs generally referred to as “sonosensitisers”produce ROS that generate the cytotoxic effect to kill the tumor cell.Sonodynamic therapy provides much greater tissue depth that can bereached non-invasively by ultrasound as compared to in over photodynamictherapy. In one aspect, the sensitizer 908 may comprise 5-aminolevulinicacid (5-ALA) among other sensitizers 908 such as hematoporphyrin, RoseBengal, curcumin, titanium nanoparticles, chlorine e6, and anycombinations thereof. In addition, the sonodynamic process may compriseinjecting microbubbles into the tumor tissue to “seed” cavitation,enabling bubble to accumulate in the tumor tissue, or injecting a drugto oxygenate tumor tissue. The sonodynamic therapy process describedherein may be combined with one or more other adjuvant therapies such aschemotherapy, immunotherapy, radiotherapy, and/or HIFU.

The non-invasive sonodynamic therapy system 900 may be employed to treata variety of tumors and to treat the area around the tumor cavity,whether malignant or nonmalignant. The area around the tumor cavityincludes cells that cause the recurrence and eventual mortality inmalignant tumors. In one aspect, the non-invasive sonodynamic therapysystem 900 may be configured to treat prostate cancer via trans-rectalultrasound sonodynamic therapy and cervical cancer via trans-vaginalultrasound sonodynamic therapy, for example.

In one aspect, the controller 902 may be configured to drive theultrasonic transducer array 904. The controller 902 may be configured toexecute one or more than one control algorithm setup/reflectionassessment and tune the drive frequency to skull thickness. This can bedone automatically. In one aspect, the control algorithm may beconfigured to pulse or control the “duty cycle” of the ultrasonictransducer array 904 drive waveform to generate high temporal peakacoustic intensity of ultrasonic acoustic waves with low temporalaverage acoustic intensity sufficient to activate the sensitizer 908while preventing thermal necrotic death of the tumor cells in thetreatment region. In another aspect, the control algorithm may beconfigured to generate packets of waves that are delayed to overlap thetumor. In another aspect, the control algorithm may be configured tocontrol the intensity of the ultrasonic acoustic wave.

In another aspect, the control algorithm may be configured to controlthe phase of the ultrasonic acoustic wave. In another aspect, thecontrol algorithm may be configured to randomize the phase of theultrasonic acoustic wave. Modulating acoustic waves with phaserandomization promotes broad consistent coverage across a treatmentregion where acoustic wavefronts constructively combine at varyingpseudo random locations within the treatment region, rather than theexact same location with each cycle. This control scheme provides a morehomogeneous treatment region to aid broad consistent treatment coverageand avoid sub therapeutic dead spots in the treatment region. Phaserandomization provides additional benefit in adapting to the treatmentenvironment. Repeating the exact same excitation pattern in some typesof acoustical environments could lead to the potential for standingwaves to form. Standing waves are inherently dangerous as they candeliver unintended treatment energy to the patient. A controller schemethat provides phase randomization of the acoustic waveform can mitigatethe risks of repetitive excitation that can lead to standing waves.

A feedback loop may be provided back to the controller 902 to adjust thedrive signal to the ultrasonic transducer array 904 based on in situvariables such as tissue depth, tissue thickness, tissue volume, skullthickness, temperature, among other variables. In one aspect, thecontroller 902 may be located in an ultrasonic generator or may belocated elsewhere. In various aspects, in situ variables may include adisease state or an inner body location. The disease state may includealternative treatment ultrasonic transducer probe that is drivendifferently for each disease state. Examples of feedback loops aredescribed hereinbelow in connection with FIGS. 22-24 .

In one aspect, the ultrasonic transducer array 904 may be configuredaccording to the transducers 150, 400, 450 described hereinabove. Invarious aspects, however, the form factor of the ultrasonic transducerarray 904 may be configured to couple ultrasonic acoustic waves invarious locations on the patient's body other than the head. Forexample, the ultrasonic transducer array 904 may be configured togenerate ultrasound that activates a sensitizer 908 to treat tumors inthe brain, such as glioblastoma, lung, breast, stomach, liver, pancreas,intestines, rectum, colon, vagina, testes, among others, whether thetumors are malignant or nonmalignant.

In various configurations, the ultrasonic transducer array 904 isnon-invasive and produces ultrasonic acoustic waves capable of reachingthe target tumor cells non-invasively. As described hereinabove, theultrasonic transducer array 904 may be configured as annular array, 2Dgrid array, a linear array, and the like, to generate an adaptivelyfocused ultrasonic acoustic wave optimized based on in situ variablessuch as tissue depth, tissue thickness, tissue volume, skull thickness,among other variables. In other aspects, the ultrasonic transducer array904 may adaptively focus or adjust the ultrasonic acoustic wave based onpretreatment planning or safety. In one aspect, the controller 902executes a control algorithm to generate selectivelyconvergent/divergent ultrasonic acoustic waves including adaptive focusfor collaborative transducer performance. The ultrasonic acoustic array904 may be configured to perform transmitter and receiver functions thatmay be controlled by the controller 902.

The ultrasonic transducer array 904 is coupled to the patient interface906 to facilitate acoustic coupling of the ultrasonic vibrationsgenerated by the ultrasonic transducer array 904 into the patient'sbody. The patient interface 906, like the ultrasonic transducer array904, is non-invasive. In one aspect, the patient interface 906 may beconfigured to remove air between the ultrasonic transducer array 904 andthe patient's body to facilitate acoustic coupling. In one aspect, thepatient interface 906 may be configured to remove excess heat from thepatient's body. In some configurations, the patient interface 906 maycomprise a variety of sensors, such as a temperature sensor, forexample. Signals from such sensors may be provided as feedback to thecontroller 902 (see FIG. 22 for example). Such feedback may be employedto control the ultrasonic transducer array 904 to generate a desiredultrasonic acoustic wave. The patient interface 906 also may include gelor hydrogel layers to improve the acoustical coupling between theultrasonic transducer array 904 and the patient's body. In one aspect,the patient interface 1022 may be configured to locally apply cooling.In one aspect, the patient interface 1022 may be configured for sensorfeedback to the processing unit 902.

Finally, the non-invasive sonodynamic therapy system 900 comprises asensitizer 908 that may be absorbed by the tumor cells. Sonodynamictherapy requires the combination of the sensitizer 908, such as asensitizing drug, ultrasound generated by the ultrasonic transducerarray 904 coupled into the patient's body by the patient interface 906,and molecular oxygen. Although these components are non-toxicindividually, when combined together, a cytotoxic ROS is generated tokill the tumor cells. Sonodynamic therapy may be configured to providepenetration of ultrasound through the patient's body and can be used totreat a wide array of deep and hard to access tumors.

FIG. 21 is an illustrative diagram 1000 of the sonodynamic therapysystem 900 shown in FIG. 20 , according to at least one aspect of thepresent disclosure. In one aspect, the sonodynamic therapy system 900comprises a controller 902 that may be located in an ultrasonicgenerator 1002. The ultrasonic generator 1002 comprises a controller1012, a user interface 1004, a foot switch 1006 for activating thecontroller 1012, and a cap or helmet 1008 that is placed over the headof the patient. A cable 1010 that carries electrical signals to and fromthe ultrasonic transducer array 904 couples the transducer array 904 andthe ultrasonic generator 1002. The ultrasonic transducer array 904comprises an array of ultrasonic transducers 150, 400, 450 placed over apatient interface 906 such as the skull cap 160. The ultrasonicgenerator 1002 drives the ultrasonic transducers 150, 400, 450 togenerate an ultrasonic acoustic wave 200 that is coupled into the bodyof the patient to excite the sensitizer 908 ingested by the patient andabsorbed by the tumor cells. The controller 1012 shapes the acousticwave to achieve a convergent, divergent, or planar acoustic wave, ormore complex acoustic waves. As previously described, in one aspect thesensitizer 908 may comprise and ALA sensitizing drug that is activatedin a sonoluminescence process, for example.

FIG. 22 is a schematic diagram 1100 of the sonodynamic therapy system900 shown in FIGS. 20 and 21 , according to at least one aspect of thepresent disclosure. The controller 902 of the sonodynamic therapy system900 comprises a user interface 1102 coupled to a processing unit 1104and configured to receive input from a user and providing output to theuser. The processing unit 1104 may be a processor or microcontrollercoupled to a memory, a control circuit, or a combination thereof. Theultrasonic transducer array 904 comprises one or more than oneultrasonic transducer 1114 and one or more than one monitoringultrasonic transducer 1116. It will be appreciated that the sameultrasonic transducer element may be configured to implement anultrasonic transmitter function as well as a receiver function (see FIG.24 for example). The patient interface 906 comprises one or more thanone temperature sensors 1118 to monitor the temperature of the patient1122. The patient interface 906 also comprises a cooling system 1120 toreduce the temperature of the patient 1122. In one aspect, the patientinterface 906 may be configured to eliminate air gaps between thetransducer 1114 and the patient 1122 to enable acoustical coupling.

The processing unit 1104 is configured to execute machine executableinstructions to implement various control algorithms as previouslydescribed. The processing unit 1104 may comprise a memory to store suchmachine executable instructions and processing engines to execute thecontrol algorithms. The processing unit 1104 also may be implemented inhardware with digital and analog electronic components. The processingunit 1104 is coupled to a multiplexing system 1112 and a power source1106 suitable for driving the ultrasonic transducers 1114.

The ultrasonic transducers 1114 are coupled to the body of the patient1122 to activate the sensitizer 908 administered to the patient 1122. Inone aspect, at least one sonosensitizer 908 agent may be configured forpreferential accumulation in selective tissue of the patient 1122.Monitoring ultrasonic transducers 1116 monitor acoustic feedback fromthe patient 1122 and generate signals that are provided as feedback tothe processing unit 1104 via an analog-to-digital converter 1110 (ADC).In addition to the acoustic feedback, a power monitoring device 1108monitors the power source 1106 and provides feedback to the processingunit 1104 through the ADC 1110. The processing unit 1104 controls theultrasonic transducer drive signals based on the acoustic feedbacksignal and/or the power monitoring signal to achieve a desiredultrasonic acoustic wave inside the body of the patient 1122. In oneaspect, at least one ultrasonic transducer 1114 is configured to outputselectively convergent and divergent acoustic waves. The transducer 1114may be configured in an annular array or a grid array. The transducer1114 may be configured with multiple electrodes. The transducer 1114 maybe configured to receive reflected acoustical signals.

The processing unit 1104 is coupled to the temperature sensors 1118 andreceives patient temperature feedback through the ADC 1010. Theprocessing unit 1104 controls the cooling system 1120 based at least inpart on the patient temperature feedback signal.

In one aspect, the processing unit 1102 is configured to produce apulsed acoustical signal with temporal-average intensity output below 8W/cm². The processing unit 1102 is adapted to apply amplitude-modulatedacoustical signals including constructive interference over a pluralityof wave cycles. The processing unit 1102 further may be configured tooutput packets of acoustic waves at various delayed sequences to providediffused tissue coverage. The processing unit 1102 may be configured toexecute frequency adaptive algorithms to optimize transmission ofacoustical signals. The processing unit 1102 may be configured tocontrol phased randomization of acoustical signals.

In various aspects, the present disclosure provides a sonodynamictherapy device comprising a transducer 904, a patient interface 906, anda controller 902 adapted to activate a sensitizer 908 within the body ofthe patient 1122. The transducer 904 may comprise one or more than onetransducer 1114, 1116 where the controller 902 is configured to generatea broadband range of ultrasonic frequencies to drive the transducer 904and produce divergent, convergent, or planar acoustic waves.

In one aspect, the patient interface 906 is configured to transmitacoustic waves produced by the transducer(s) 904 into the body of thepatient 1122 thus acoustically coupling the transducer(s) 904 to thepatient 1122. In one aspect, the patient interface 906 provides acooling system 1120 to remove any excess heat that builds up in thepatient 1122 as a of the coupling acoustic energy to the body of thepatient 1122. In one aspect, the patient interface 906 may comprise anintegral cooling system 1120. The patient interface 906 may comprise ahydrogel cap filled with gel or a water-filled cap with coolingchannels. In one aspect, the patient interface 906 comprises one or morethan one sensor 1118 to provide feedback to the processing unit 1104 ofthe controller 902. The sensors 1118 may include, for example,temperature sensors, optical temperature sensors to measure temperaturein a particular direction, acoustic sensors, which may include the sametransducers 904 used for transmitting acoustic signals. The patientinterface 906 may be configured to remove air from the patient interface906 to improve acoustic coupling between the transducer 904 and the bodyof the patient 1122. In anther aspect, the patient interface 906 may beconfigured to cool the patient 1122. In yet another aspect, the patientinterface 906 may be configured to cool the transducers 904, forexample, to keep the transducers at the same temperature to achievefrequency stability.

In one aspect, the patient interface 906 may be adapted and configuredto fit various patient anatomies. For example, the patient interface 906may be adapted and configured to fit patient anatomies for sonodynamictherapy specifically adapted to treat tumors located in the brain, lung,breast, stomach, liver, pancreas, intestines, rectum, colon, vagina,testes, among others, for example. A sonodynamic therapy device may beadapted to wrap around the torso or limb of the patient and/or employedto treat osteosarcoma into the bone. The controller 902 may be adaptedto detect either the patient interface 906 or the sonodynamic therapydevice such as the transducer 904 or patient interface 906 and select atreatment algorithm to produce acoustic waves optimized for treating thevarious tumors. The transducer 904 or patient interface 906 may beidentified using identification (ID) circuits 1115, 1119 comprising asingle-wire serial EEPROM, for example. The ID circuit 1115, 1119 EEPROMmay contain both a preprogrammed unique serial number and memorysections. Any or all of the memory sections can be permanently locked bythe end-equipment manufacturer to allow tracking of products andidentifying attachments. Other identification techniques may includedetecting the impedance of the transducer 904 or patient interface 906and associating the impedance with a treatment algorithm.

In one aspect, the controller 902 is configured to generate electricaldrive signals to actuate one or more than one ultrasonic transducer 904to produce an acoustic wave to activate a sensitizer 908 located withinthe body of the patient 1122. In one aspect, the electrical drivesignals generated by the controller 902 may actuate the one or more thanone ultrasonic transducer 904 to produce acoustic waves of varyingintensities, amplitudes, or frequencies. In another aspect, the acousticwaves may be amplitude modulated, frequency modulated, phase modulated,continuous, discontinuous, pulsed, randomized, or combinations thereof.In other aspects, the acoustic waves my be produced in a packet of wavecycles, where the number of cycles per packet may be predetermined toachieve a desired outcome that is different from a focused ultrasoundpulse, for example. In other aspects, the controller 902 is configuredto generate a frequency modulation signal to produce afrequency-modulated acoustic wave. In one aspect, the controller may beconfigured to generate an intra or inter pulse variation signal that canbe used to reduce standing acoustic waves.

In one aspect, the controller 902 is configured to apply anamplitude-modulated acoustic ultrasound signal which constructivelyinterferes over a plurality of wave cycles. In one aspect, the intensityof each of the plurality of acoustic waves remain within a safe rangewherein the ultrasound energy carried by each of the plurality ofacoustic waves is safe to the tissue of the patient 1122, such as thebrain or other body part. In one aspect, the controller 902 may beconfigured to drive the transducer 904 to generate anamplitude-modulated acoustic wave which produces a constructivewavefront.

In one aspect where the sonodynamic therapy device comprises onetransducer 904 and the controller 902 may be configured to generate adrive signal to actuate the transducer 904 to produce a long acousticultrasonic wave packet In one aspect, the controller 902 may beconfigured to generate a drive signal to actuate the transducer 904 toproduce an ultrasonic acoustic wave packet composed of a sinusoidal waveamplitude modulated by a Gaussian pulse (see FIG. 10 for example). Inanother aspect, the controller 902 may be configured to generate a drivesignal to actuate the transducer 904 to produce an ultrasonic acousticwave packet composed of a sinusoidal wave amplitude modulated by arectangular pulse. In another aspect, the controller 902 may beconfigured to generate a drive signal to actuate the transducer 904 toproduce an ultrasonic acoustic wave packet composed of a sinusoidal waveamplitude modulated by a triangular pulse. The ultrasonic acoustic wavepacket may comprise intra or inter wave packet variation. In one aspect,the controller 902 may be configured to generate a drive signal toactuate the transducer 904 to produce an acoustic ultrasonic pulse. Theacoustic wavefronts of the ultrasonic pulse may either converge to focusthe ultrasonic energy to a specific region or diverge to spread theultrasonic energy to a larger region.

In other aspects, where the sonodynamic therapy device comprises two ormore transducers 904 and the controller 902 may be configured togenerate a drive signal to actuate the two or more transducers 904 toproduce acoustic ultrasonic pulses where the individual wavefronts,whether converging or diverging, will meet at the same location at thesame time to focus the ultrasonic energy. In one aspect, the controller902 may adapt the frequency drive for each transducer 904.

FIG. 23 is a schematic diagram of a sonodynamic therapy system 920 witha separate transmitter transducer 930 and receiver transducer 934,according to at least one aspect of the present disclosure. Thesonodynamic therapy system 920 comprises a system controller 922 tocontrol a signal generator 924 to generate an electrical signal to drivethe transmitter transducer 930. The electrical signal is amplified by anamplifier 926 and the drive signal is coupled to the transmittertransducer 930 by a matching network 928 to maximize power transferredto the transmitter transducer 930. The transmitter transducer 930transmits an acoustic wave into tissue 932 (e.g., lesions) in thetreatment region. A receiver transducer 934 detects acoustic wavesemitted by the tissue 932. The output of the receiver transducer 934 isa weak electrical signal that is provided to an electronic pre-amplifier936 that converts the weak electrical signal into an output signalstrong enough to be noise-tolerant and strong enough for furtherprocessing such as filtering by a filter 938. The output of the filter938 is provided to an analog-to-digital converter 940 (ADC) thatprovides a feedback signal to the system controller 922 in digital form.Based on the feedback signal received from the receiver transducer 934the system controller 922 can adjust the drive signal applied to thetransmitter transducer 930. The adjustment may include adjusting themodulation, strength, frequency, phase, or randomization, of the drivesignal, or any combinations thereof. The feedback signal may representtissue depth, tissue thickness, tissue volume, skull thickness,temperature, distance to the treatment region, or a combination thereof.

FIG. 24 is a schematic diagram of a sonodynamic therapy system 950 witha single transmitting and receiving transducer 962, according to atleast one aspect of the present disclosure. The sonodynamic therapysystem 950 comprises a system controller 952 to control a signalgenerator 954 to generate an electrical signal to drive the transducer962 in transmitter mode. The electrical signal is amplified by anamplifier 956 and is applied to a transmitter/receiver (T/R) switch 958.When the transducer 962 is in transmitter mode, the T/R switch 958couples the drive signal to the transducer 962 via a matching network960 to optimize power transferred to the transducer 962. In transmittermode, the transducer 962 transmits an acoustic wave into tissue 964(e.g., lesions) in the treatment region. In receiver mode, thetransducer 962 detects acoustic waves emitted by the tissue 964. Theoutput of the transducer 962 is a weak electrical signal that is coupledto the T/R switch 958 by the matching network 960. The T/R switch 958provides the weak electrical signal to an electronic pre-amplifier 966that converts the weak electrical signal into an output signal strongenough to be noise-tolerant and strong enough for further processingsuch as filtering by a filter 968. The output of the filter 968 isprovided to an ADC 970 that provides a feedback signal to the systemcontroller 952 in digital form. Based on the feedback signal receivedfrom the transducer 962 in receiver mode, the system controller 952 canadjust the drive signal applied to the transducer 962 in transmittermode. The adjustment may include adjusting the modulation, strength,frequency, phase, or randomization, of the drive signal, or anycombinations thereof. The feedback signal may represent tissue depth,tissue thickness, skull thickness, temperature, distance to thetreatment region, or a combination thereof.

Having described various aspects of a sonodynamic therapy system 920,950, 1100 and components of the sonodynamic therapy system 920, 950,1100, the disclosure now turns to a description of a sonodynamic therapyprocess that can be implemented with the sonodynamic therapy systems920, 950, 1100 described hereinabove. For conciseness and clarity ofdisclosure, a sonodynamic therapy process according to FIGS. 25-31hereinbelow will be described in connection with FIGS. 20-24 .

FIG. 25 is an overview of a sonodynamic therapy process 1200, accordingto at least one aspect of the present disclosure. In a first phase 1202of the sonodynamic therapy process, the patient is administered asonodynamic sensitizer 908 as described herein, and dons an ultrasonictransducer array 904 comprising a plurality of ultrasonic transducers150. The sonodynamic sensitizer 908 may be administered orally orthrough other natural orifices, by injection, intravenously, topically,or other suitable technique. In a second phase 1204 of the sonodynamictherapy process, the sonodynamic sensitizer 908 accumulates in tumorcells 1206. In a third phase 1208 of the sonodynamic therapy process1200, an ultrasound acoustic wave 1210 generated by the ultrasonicgenerator 1002 activates the sonodynamic sensitizer 908. In a fourthphase 1212 of the sonodynamic therapy process 1200, the sonodynamicsensitizer 908 instigates a sequence of death of a tumor cell 1206.

FIG. 26 is a diagram 1300 of a tumor cell 1206 illustrating the initialstage of selective accumulation of a sensitizer 908, according to atleast one aspect of the present disclosure. In the illustrated example,the sensitizer 908 is absorbed 1302 into the mitochondria 1304 of thecancer cell 1206. The patient is administered 5-ALA, pro drug sensitizer908, orally, which puts the heme 1306 biosynthesis pathway 1316 intooverdrive. In general, the body's natural feedback mechanism preventsthe production of too much heme 1306. Heme 1306 will result in loweractivity of the aminolevulinic acid synthase (ALAS) enzyme whichproduces 5-ALA endogenously. By introducing the sensitizer 908exogenously, heme 1306 biosynthesis keeps producing even though the ALASenzyme is inactivated. As a result, protoporphyrin IX 1308 (PpIX)accumulates preferentially in many types of cancer cells 1206 includingglioblastoma multiforme (GBM). PpIX 1308 is a catalyst that convertsdissolved molecular oxygen into ROS by absorbing photons. ProtoporphyrinIX 1308 is in the same class of molecules as chlorophyll (i.e.,porphyrins), and is capable of converting light into chemical energy.

FIG. 27 is a diagram 1320 of the cancer cell 1206 illustrating theincreased selective accumulation 1322 of the sensitizer 908, accordingto at least one aspect of the present disclosure. As shown in FIG. 27 ,the PpIX 1308 is an active compound and the second to last intermediateproduct in the heme 1306 biosynthesis pathway 1316. The accumulation ofPpIX 1308 in the cancer cell 1206 mitochondria 1304 is due to increasedaccumulation 1322 of the 5-ALA sensitizer 908 and reduced conversion ofPpIX 1308 into heme 1306 (reduced expression of ferrochelatase).

FIG. 28 is a diagram 1330 of the cancer cell 1206 shown in FIGS. 26 and27 undergoing sonodynamic therapy, according to at least one aspect ofthe present disclosure. The ultrasonic transducer 904 generates anultrasound acoustic wave 200 that penetrates the cancer cell 1206 andthe mitochondria 1304. The ultrasound acoustic wave 200 produces light1312 through a process called sonoluminescence. Sonoluminescence occurswhen the ultrasound acoustic wave 200 collapses fluid bubbles 1332causing cavitation 1334 and produces light 1312 in the process. Theproduction of light 1312 happens far away from the ultrasonic transducer904. The light 1312 produced through sonoluminescence activates the PpIX1308 to produce ROS 1336. Sonoluminescence can occur anywhere theintensity of the ultrasound acoustic wave 200 is sufficient, whichallows sonodynamic therapy to treat much deeper than photodynamictherapy. The ROS 1336 species cause oxidative stress which results inthe cancer cell 1206 undergoing programmed cell death 1314 (apoptosis),which is the same as photodynamic therapy.

FIG. 29 is a diagram 1400 illustrating the sonoluminescence process,according to at least one aspect of the present disclosure. The diagram1400 can be found in Detlef Lohse, Sonoluminescence, Inside amicro-reactor, Nature volume 418, pages 381-383 (2002), which isincorporated herein by reference. In a standing ultrasonic acoustic wave200, at low sound-wave pressure, a gas bubble 1402 expands dramatically,until an increase in sound-wave pressure triggers a collapse of the gasbubble 1402. As the temperature inside the gas bubble 1402 soars to over10,000 K, the gas in the bubble 1402 becomes partly ionized, forming aplasma 1404. Finally, recombination of electrons and ions results inlight emission 1406.

FIG. 30 is a schematic diagram 1500 of a cancer cell 1502 illustratingthe selective accumulation of a sensitizer 908, according to at leastone aspect of the present disclosure. In the illustrated example, the5-ALA sensitizer 908 is systematically administered into the cancer cell1502 and is absorbed into the mitochondria 1504 of the cancer cell 1502.The 5-ALA sensitizer 908 is administered to the patient orally, whichputs the heme 1506 biosynthesis pathway into overdrive. The naturalfeedback mechanism of the patient's body prevents the production of toomuch heme 1506. Heme 1506 will result in lower activity of theaminolevulinic acid synthase (ALAS) enzyme which produces 5-ALAendogenously. By introducing the ALA sensitizer 908 exogenously, heme1506 biosynthesis keeps producing even though the ALAS enzyme isinactivated. As a result, PpIX 1508 accumulates preferentially in manytypes of cancer cells 1502 including glioblastoma multiforme (GBM).

The PpIX 1508 is an active compound and the second to last intermediateproduct in the heme 1506 biosynthesis pathway 1510. The accumulation ofPpIX 1508 in the cancer cell 1502 mitochondria 1504 is due to increaseduptake of the 5-ALA sensitizer 908 and reduced conversion of PpIX 1508into heme 1506 reduced expression of ferrochelatase 1512.

The PpIX 1508 is a catalyst that converts dissolved molecular oxygeninto ROS by absorbing photons. Protoporphyrin IX 1508 is in the sameclass of molecules as chlorophyll (i.e., porphyrins), and is capable ofconverting light into chemical energy.

FIG. 31 is a schematic diagram 1600 of the cancer cell 1502 shown inFIG. 30 undergoing sonodynamic therapy, according to at least one aspectof the present disclosure. The ultrasonic transducer 904 generates anultrasound acoustic wave 200 that penetrates the cancer cell 1502 andthe mitochondria 1504. The ultrasound acoustic wave 200 produces light1602 through cavitation 1606 and a process called sonoluminescence 1604.The production of light 1602 happens far away from the ultrasonictransducer 904. The light 1602 produced through sonoluminescence 1604activates the PpIX 1508 to produce ROS 1608. Sonoluminescence 1604 canoccur anywhere the intensity of the ultrasound acoustic wave 200 issufficient, which allows sonodynamic therapy to treat much deeper thanphotodynamic therapy. The ROS 1608 species cause oxidative stress whichresults in the cancer cell 1502 undergoing programmed cell death 1610(apoptosis), which is the same as photodynamic therapy.

The interaction of acoustic waves 200 with an aqueous medium may resultin cavitation 1606. Cavitation 1606 involves nucleation, growth, andimplosive collapse of gas-filled bubbles, under the appropriateultrasound conditions. In sonoluminescence 1604, inertial cavitation1606 involves the growth of gas bubbles to a near resonance size andexpanding to a maximum before collapsing violently. The energy releasedby this implosion results in temperatures of up to 10,000 K andpressures of up to 81 MPa in the surrounding microenvironment. Suchextreme temperatures and pressures at the point of implosion create asono-chemical reactor. Cavitation 1606 generates ROS 1608 in sonodynamictherapy under two mechanisms of action.

One possible mechanism of action is sonoluminescence 1604. This isprocess upon which light 1602 is generated upon exposure of the cancercell 1502 energy produced by the acoustic wave 200. Another possiblemechanism of action may be pyrolysis. This is a process wherebylocalized temperature elevation that accompanies inertial cavitation1606 breaks apart the sensitizer 908 generating free radicals that canreact with other endogenous substrates to generate ROS 1608. AlthoughROS 1608 plays an important role is SDT, in some aspects sonodynamictherapy may be based on sonomechanical mechanisms. This conclusion wasbased on their observation that HP-sensitized cells can be sensitive tothe acoustic wave 200 at intensities that were shown not to induceinertial cavitation.

In various aspects of the present disclosure, sonodynamic therapy may becarried out using one or more than one sensitizer 908. Such sensitizers908 used in sonodynamic therapy may be selected from a variety ofcompounds. These compounds include, without limitation, porphyrins suchas Photofrin, protoporphyrin IX precursor, xanthene-based sensitizers908 such as Rose Bengal and derivatives thereof, acridine orange,methylene blue, curcumin, hypocrellin, indocyanine green,nanoparticle/microparticle sensitizer conjugates. Additional informationon sonodynamic therapy may be found in Treating Cancer With SonodynamicTherapy: A Review, David Costley et al., pages 107-117, received 17 Oct.2014, accepted 23 Nov. 2014, published online 13 Jan. 2015, which isherein incorporated by reference in its entirety. In various aspects,the sonodynamic therapy techniques described in this disclosure may beapplied to animals as well as humans. In one aspect, the sonodynamictherapy techniques descried in this disclosure may be applied tomammals. In this regard, use of the term “patient” throughout thisdisclosure is intended to cover humans and animals alike.

In various aspects, the sonodynamic therapy techniques described in thisdisclosure may be adapted to other parts of the body. These other partsof the body may be accessed through natural orifice (mouth, nasalcavity, anus, vagina) or minimally invasive processes such asintravascular access. The sonodynamic therapy device may be specificallyadapted to have a flexible, navigable catheter shaft to reach tumors inspecific organs such as liver, stomach, breast, or lungs, for example.The sonodynamic therapy device may be adapted to wrap around the torsoor limb and may be employed to treat osteosarcoma into the bone.

In various aspects, the sonodynamic therapy techniques described in thisdisclosure may be adapted for use with adjuvant therapies. The disclosedsonodynamic therapy techniques may be employed in other cancer therapiesincluding chemotherapy, immunotherapy, radiotherapy, HIFU/hyperthermia.Further, the disclosed sonodynamic therapy techniques employ additionaldrugs which increase oxygen in the brain or increase oxygen in a braintumor to a preferential oxygen concentration to provide an effectivesonodynamic therapy. The disclosed sonodynamic therapy techniques mayemploy a sensitizer which is modified or encapsulated to effectivelytarget a tumor. The disclosed sonodynamic therapy techniques may deliver0 2 systematically with nose tubes. The disclosed sonodynamic therapytechniques may employ multiple sensitizers in conjunction and mayinclude the introduction of gas bubbles into the tumor to oxygenate thetumor, create more cavitation, and provide a possible contrast mechanismfor imaging.

In various aspects, the sonodynamic therapy techniques described in thisdisclosure may be adapted for use with ultrasound imaging. The processmay include the addition of a contrast agent for ultrasound which goesto the tumor.

As used herein a processor or processing unit is an electronic circuitwhich performs operations on some external data source, usually memoryor some other data stream. The term is used herein to refer to thecentral processor (central processing unit) in a system or computersystems (especially systems on a chip (SoCs)) that combine a number ofspecialized “processors.”

As used herein, a system on a chip or system on chip (Soc or SOC) is anintegrated circuit (also known as an “IC” or “chip”) that integrates allcomponents of a computer or other electronic systems. It may containdigital, analog, mixed-signal, and often radio-frequency functions-allon a single substrate. A Soc integrates a microcontroller (ormicroprocessor) with advanced peripherals like graphics processing unit(GPU), Wi-Fi module, or coprocessor. A Soc may or may not containbuilt-in memory.

As used herein, a microcontroller or controller is a system thatintegrates a microprocessor with peripheral circuits and memory. Amicrocontroller (or MCU for microcontroller unit) may be implemented asa small computer on a single integrated circuit It may be similar to aSoc; an Soc may include a microcontroller as one of its components. Amicrocontroller may contain one or more core processing units (CPUs)along with memory and programmable input/output peripherals. Programmemory in the form of Ferroelectric RAM, NOR flash or OTP ROM is alsooften included on chip, as well as a small amount of RAM.Microcontrollers may be employed for embedded applications, in contrastto the microprocessors used in personal computers or other generalpurpose applications consisting of various discrete chips.

As used herein, the term controller or microcontroller may be astand-alone IC or chip device that interfaces with a peripheral device.This may be a link between two parts of a computer or a controller on anexternal device that manages the operation of (and connection with) thatdevice.

Any of the processors or microcontrollers described herein, may beimplemented by any single core or multicore processor such as thoseknown under the trade name ARM Cortex by Texas Instruments. In oneaspect, the processor may be an LM4F230H5QR ARM Cortex-M4F ProcessorCore, available from Texas Instruments, for example, comprising on-chipmemory of 256 KB single-cycle flash memory, or other non-volatilememory, up to 40 MHz, a prefetch buffer to improve performance above 40MHz, a 32 KB single-cycle serial random access memory (SRAM), internalread-only memory (ROM) loaded with StellarisWare® software, 2 KBelectrically erasable programmable read-only memory (EEPROM), one ormore pulse width modulation (PWM) modules, one or more quadratureencoder inputs (QEI) analog, one or more 12-bit Analog-to-DigitalConverters (ADC) with 12 analog input channels, details of which areavailable for the product datasheet

In one aspect, the processor may comprise a safety controller comprisingtwo controller-based families such as TMS570 and RM4x known under thetrade name Hercules ARM Cortex R4, also by Texas Instruments. The safetycontroller may be configured specifically for IEC 61508 and ISO 26262safety critical applications, among others, to provide advancedintegrated safety features while delivering scalable performance,connectivity, and memory options.

As used herein, the terms “component,” “system,” “module” and the likecan refer to a computer-related entity, either hardware, a combinationof hardware and software, software, or software in execution, inaddition to electro-mechanical devices. For example, a component may be,but is not limited to being, a process running on a processor, aprocessor, an object, an executable, a thread of execution, a program,and/or a computer. By way of illustration, both an application runningon computer and the computer can be a component. One or more componentsmay reside within a process and/or thread of execution and a componentmay be localized on one computer and/or distributed between two or morecomputers. The word “exemplary” is used herein to mean serving as anexample, instance, or illustration. Any aspect or design describedherein as “exemplar” is not necessarily to be construed as preferred oradvantageous over other aspects or designs.

As used herein, the term control circuit may be any stand alone orcombination electronic circuit such as, for example, a processing unit,processor, microcontroller, microcontroller unit, controller, digitalsignal processor (DSP), programmable gate array (PGA), field PGA (FPGA),programmable logic device (PLD), system on chip (SoC), applicationspecific integrated circuit (ASIC), graphics processing unit (GPU), andthe like. According to various aspects, process flow diagrams describedherein may be implemented by a digital device such as a control circuit.

Although the various aspects of the present disclosure describeinstruction handling and distribution in the context of execution unitsand logic circuits, other aspects of the present disclosure can beaccomplished by way of data and/or instructions stored on amachine-readable, tangible medium, which when performed by a machinecause the machine to perform functions consistent with at least oneaspect. In one aspect, associated functions of the present disclosureare embodied in machine-executable instructions. The instructions can beused to cause a general-purpose or special-purpose processor that isprogrammed with the instructions to perform the steps of the functionsdescribed in the present disclosure. Aspects of the present disclosuremay be provided as a computer program product or software which mayinclude a machine or non-transitory computer-readable medium havingstored thereon instructions which may be used to program a computer (orother electronic devices) to perform one or more operations according toaspects of the present disclosure. Alternatively, functions according tothe present disclosure might be performed by specific hardwarecomponents that contain fixed-function logic for performing thefunctions, or by any combination of programmed computer components andfixed-function hardware components.

Instructions used to program logic to perform various disclosed aspectscan be stored within a memory in the system, such as DRAM, cache, flashmemory, or other storage. Furthermore, the instructions can bedistributed via a network or by way of other computer readable media.Thus a machine-readable medium may include any mechanism for storing ortransmitting information in a form readable by a machine (e.g., acomputer), but is not limited to, floppy diskettes, optical disks,Compact Disc, Read-Only Memory (CD-ROMs), and magneto-optical disks,Read-Only Memory (ROMs), Random Access Memory (RAM), ErasableProgrammable Read-Only Memory (EPROM), Electrically ErasableProgrammable Read-Only Memory (EEPROM), magnetic or optical cards, flashmemory, or a tangible, machine-readable storage used in the transmissionof information over the Internet via electrical, optical, acoustical orother forms of propagated signals (e.g., carrier waves, infraredsignals, digital signals, etc.). Accordingly, the non-transitorycomputer-readable medium includes any type of tangible machine-readablemedium suitable for storing or transmitting electronic instructions orinformation in a form readable by a machine (e.g., a computer).

Various examples have been described with reference to certain disclosedaspects. The various aspects are presented for purposes of illustrationand not limitation. One skilled in the art will appreciate that variouschanges, adaptations, and modifications can be made without departingfrom the scope of the disclosure or the scope of the appended claims.

What is claimed is:
 1. A method of producing zero vergence ultrasoundwaves for sonodynamic therapy to treat tumor cells harboring asonosensitizer, comprising: coupling a sonodynamic therapy device to askin surface over a treatment region with the tumor cells of a patient,the sonodynamic therapy device comprising a flexible membrane coupled toa shell and a cooling system, wherein the shell comprises an array ofpiezoelectric ultrasound transducer elements, wherein the array ofpiezoelectric ultrasound transducer elements is coupled to a controller,wherein each of the piezoelectric ultrasound transducer elements isconfigured to emit a zero vergence ultrasound wave that delivers aplanar ultrasound wave to the tumor cells, driving the array ofpiezoelectric ultrasound transducer elements with a signal to activatethe sonosensitizer in the tumor cells of the patient, wherein the signalis configured to minimize a spatial variation of an acoustic intensityin the treatment region with the tumor cells of the patient with amodulated wave parameter to emit the zero vergence ultrasound wave withthe acoustic intensity to damage the tumor cells in the treatment regionof the patient, wherein the sonodynamic therapy device is configured toacoustically couple the array of piezoelectric ultrasound transducerelements to the skin surface, wherein the flexible membrane isconfigured for conforming to the patient at the skin surface; whereinthe driving the array of piezoelectric transducer elements comprisesphase randomization to promote broad coverage of the treatment region bya plurality of the planar ultrasound waves, and circulating a fluid inthe cooling system, wherein the cooling system is configured to absorbheat through the skin surface over a treatment region.
 2. The method ofclaim 1, wherein the controller determines at least one in situ variableselected from the group consisting of: a tissue depth, a tissue volume,a skull thickness, and a temperature, and adaptively modulates themodulated wave parameter to generate the zero vergence ultrasound waveoptimized based on the at least one in situ variable, wherein the signalis modulated by a frequency modulated drive signal to produce afrequency modulated acoustic wave with a variety of frequencies in arange of 650 kHz to 2 MHz configured to minimize the spatial variationof the acoustic intensity at the tumor cells of the patient whenactivating the sonosensitizer.
 3. The method of claim 1, wherein thecontroller determines an in situ variable and adaptively modulates thezero vergence ultrasound wave to preferentially target the treatmentregion based on the in situ variable, wherein the treatment regioncomprises a brain.
 4. The method of claim 1, wherein the controllerdetects at least one piezoelectric transducer element in the array ofpiezoelectric transducer elements and selects a treatment algorithm forthe at least one piezoelectric transducer element, wherein the acousticintensity within the treatment region is in a range of 0.1 W/cm² to 50W/cm² to activate the sonosensitizer.
 5. The method of claim 1, whereinthe array of flat piezoelectric ultrasound transducers comprises a gridof elements, and wherein the signal comprises at least one of the groupconsisting of: an intra pulse variation and an inter pulse variation,wherein the phase randomization is configured to drive each of thepiezoelectric ultrasound transducer elements to produce high temporalpeak acoustic intensities within the treatment region with a lowtemporal average acoustic intensity when activating the sonosensitizerfor non-thermally ablative treatment.
 6. The method of claim 1, whereinthe controller drives the array of piezoelectric transducer elementswith the signal at a variety of frequencies, to emit the zero vergenceultrasound wave with a temporal average intensity without causingthermal or other damage to healthy cells in the treatment region.
 7. Themethod of claim 1, wherein the controller drives the array ofpiezoelectric transducer elements with the signal at a variety offrequencies, phases, and delays, to emit a selectively divergentultrasound field for a non-thermally ablative treatment with a temporalaverage intensity that does not increase temperature of a healthy tissuein the treatment region above 42° C.
 8. The method of claim 1, furthercomprising: measuring a temperature with a temperature sensor in thecooling system; and varying the signal based on the temperature, whereinthe cooling system comprises the temperature sensor and an elastic,fluid-filled pocket between the flexible membrane and the shell, whereinthe fluid is water, and wherein the driving the array of piezoelectricultrasound transducer elements comprises driving multiple elements withmultiple signals.
 9. The method of claim 1, wherein the signal isfurther modulated by a duty cycle modulated drive signal configured toproduce a duty cycle modulated acoustic wave, wherein the duty cyclemodulated drive signal is configured to generate a temporal averageacoustic intensity when activating the sonosensitizer.
 10. The method ofclaim 1, further comprising circulating a fluid through a coolingchannel in the cooling system to reduce heat at the skin surface of thepatient at the flexible membrane.
 11. The method of claim 10, whereinthe fluid is configured to acoustically couple the array ofpiezoelectric ultrasound transducer elements to the flexible membrane.12. The method of claim 1, further comprising administering a pro drugto the patient, wherein the pro drug comprises 5-aminolevulinic acid(5-ALA), wherein the 5-ALA results in increased production ofprotoporphyrin IX, wherein the sonosensitizer comprises theprotoporphyrin IX.
 13. A method of producing zero vergence ultrasoundwaves for sonodynamic therapy to treat tumor cells harboring asonosensitizer, comprising: coupling a sonodynamic therapy device to askin surface over a treatment region with the tumor cells of a patient,the sonodynamic therapy device comprising a flexible membrane coupled toa shell and a cooling system, wherein the shell comprises an array ofpiezoelectric ultrasound transducer elements and a controller, whereineach of the piezoelectric ultrasound transducer elements is configuredto emit a zero vergence ultrasound wave to deliver a planar ultrasoundwave to the tumor cells, driving the array of piezoelectric ultrasoundtransducer elements with a signal to activate the sonosensitizer in thetumor cells in a brain of the patient, wherein the signal is configuredto minimize a spatial variation of an acoustic intensity in the brainwith the tumor cells of the patient with a modulated wave parameterconfigured to emit a plurality of the zero vergence ultrasound waveswith a frequency in a range of 650 kHz to 2 MHz at the acousticintensity in a range of 0.1 W/cm² to 50 W/cm² within the treatmentregion to activate the sonosensitizer in the treatment region to treatcancer in the tumor cells of the patient, wherein the signal ismodulated by a duty cycle modulated drive signal configured to produce aduty cycle modulated pulse sequence, wherein the signal comprises arandomized phase configured to drive each of the piezoelectricultrasound transducer elements to produce a high temporal peak acousticintensity with a low temporal average acoustic intensity within thetreatment region when activating the sonosensitizer, wherein thesonodynamic therapy device is configured to acoustically couple thearray of piezoelectric ultrasound transducer elements to the skinsurface, wherein the flexible membrane is configured for non-invasivelyconforming to the patient at the skin surface; and circulating a fluidin the cooling system to absorb heat through the skin surface over atreatment region.
 14. The method of claim 13, wherein the cooling systemcomprises aa conformable liquid volume between the flexible membrane andthe array of piezoelectric transducer elements, wherein driving thearray of piezoelectric ultrasound transducer elements comprises drivingmultiple elements with multiple signals.
 15. The method of claim 13,wherein the controller drives the array of piezoelectric transducerelements with the signal at the frequency to emit the zero vergenceultrasound wave with the temporal average acoustic intensity withoutincreasing a temperature of a healthy tissue in the treatment regionabove 42° C., wherein the randomized phase promotes broad coverage ofthe treatment region by the plurality of the planar ultrasound waves.16. The method of claim 13, wherein the signal is a packet comprising apredetermined number of cycles per packet to produce a packet ofacoustic waves, the signal being selected from at least one of the groupconsisting of: a frequency modulated drive signal and a phase modulatedsignal, wherein the packet is made of a repeating signal comprising atleast one selected from the group consisting of: a sine wave, arectangular pulse, and a triangular pulse.
 17. The method of claim 13,further comprising administering a pro drug to the patient, wherein thepro drug comprises 5-aminolevulinic acid (5-ALA), wherein the 5-ALAresults in increased production of protoporphyrin IX, wherein thesonosensitizer comprises the protoporphyrin IX.
 18. A method ofproducing planar ultrasound waves for sonodynamic therapy to treat tumorcells harboring a sonosensitizer, comprising: coupling a sonodynamictherapy device to a skin surface of a patient, the sonodynamic therapydevice comprising a flexible membrane attached to a shell and a coolingsystem, wherein the shell comprises an array of piezoelectric ultrasoundtransducer elements, wherein each of the piezoelectric ultrasoundtransducer elements is configured to produce a planar ultrasound wave;driving the array of piezoelectric ultrasound transducer elements with asignal with a modulated wave parameter to produce the planar ultrasoundwave with an acoustic intensity 0.5 W/cm² to 500 W/cm² in a treatmentregion to treat tumor cells, wherein the sonodynamic therapy device isconfigured to acoustically couple the array of piezoelectric ultrasoundtransducer elements to the skin surface, wherein the flexible membraneis configured for conforming to the skin surface; and circulating afluid in the cooling system to reduce heat of the patient.
 19. Themethod of claim 18, wherein the sonodynamic therapy is configured tominimize a spatial variation of the acoustic intensity in the tumorcells of the patient, wherein the signal is selected from the groupconsisting of: a phase modulated drive signal to produce a phasemodulated acoustic wave and a pulse signal to produce a pulsed acousticwave.
 20. The method of claim 18, wherein the sonodynamic therapy isconfigured to minimize a spatial variation of the acoustic intensity inthe tumor cells of the patient, wherein the signal is selected from thegroup consisting of: a duty cycle modulated drive signal to produce aduty cycle modulated acoustic wave and a frequency modulated drivesignal to produce a frequency modulated acoustic wave.